Abstract
Adenosine kinase (AK; EC 2.7.1.20) is a key intracellular enzyme regulating intra-and extracellular concentrations of adenosine (ADO), an endogenous neuromodulator, antinociceptive, and anti-inflammatory autocoid. AK inhibition provides a means of potentiating local tissue concentrations of endogenous ADO, and AK inhibitors may have therapeutic potential as analgesic and anti-inflammatory agents. The effects of ABT-702, a novel, potent (IC50 = 1.7 nM), and selective non-nucleoside AK inhibitor were examined in rat models of nociception and acute inflammation. ABT-702 was orally effective and fully efficacious to suppress nociception in a spectrum of pain models in the rat, including carrageenan-induced thermal hyperalgesia, the formalin test of persistent pain, and models of nerve injury-induced and diabetic neuropathic pain (tactile allodynia after L5/L6 spinal nerve ligation or streptozotocin injection, respectively.) ABT-702 was especially potent at relieving inflammatory thermal hyperalgesia (ED50 = 5 μmol/kg p.o.). ABT-702 was also effective in the carrageenan-induced paw edema model of acute inflammation (ED50 = 70 μmol/kg p.o.). The antinociceptive and anti-inflammatory effects of ABT-702 were blocked by selective ADO receptor antagonists, consistent with endogenous ADO accumulation and ADO receptor activation as a mechanism of action. The antinociceptive effects of ABT-702 were not blocked by the opioid antagonist naloxone. In addition, ABT-702 showed less potential to develop tolerance to its antinociceptive effects compared with morphine. ABT-702 had no significant effect on rotorod performance or heart rate (at 30–300 μmol/kg p.o.), mean arterial pressure (at 30–100 μmol/kg p.o.), or exploratory locomotor activity (at ≤10 μmol/kg p.o.). Thus, ABT-702 is a novel, non-nucleoside AK inhibitor, with a nonopioid, non-nonsteroidal anti-inflammatory drug mechanism of action, which shows antinociceptive and anti-inflammatory activity in vivo.
Footnotes
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Send reprint requests to: Michael F. Jarvis, Ph.D., D-4PM, AP9A/2, Neurological and Urological Diseases Research, Abbott Laboratories, 100 Abbott Park Rd., Abbott Park, IL 60064-6123. E-mail:michael.jarvis{at}abbott.com
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↵1 Present address: Signal Pharmaceuticals, San Diego, CA.
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↵2 D. L. Boyle, E. A. Kowaluk, M. F. Jarvis, C.-H. Lee, S. S. Bhagwat, M. Williams, and G. S. Firestein, Anti-inflammatory effects of ABT-702, a novel adenosine kinase inhibitor, in rat adjuvant arthritis. Presented at the American College of Rheumatology, Philadelphia, PA, 2000.
- Abbreviations:
- ADO
- adenosine
- AK
- adenosine kinase
- MPO
- myeloperoxidase
- CPT
- cyclopentyltheophylline
- DMPX
- 3,7-dimethyl-1-propargylxanthine
- MPE
- maximum protective effect
- Received July 6, 2000.
- Accepted August 18, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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